Ugi–Smiles Couplings of Purine Derivatives

Abstract

Purines may be involved in Ugi–Smiles coupling as shown by the successful formation of thiocarboxamide derivatives from 6-mercaptopurine. This multicomponent coupling affords a very straightforward access to functionalized adenine derivatives, which are widely represented among natural products of medicinal interest.

Key words

isocyanide - multicomponent - Ugi–Smiles - purines - adenines - thioamides

• References and Notes

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Direct formation of 6-aminopurines from 6-hydroxy derivatives may be obtained under activation with phosphonium salts such as BOP:
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The direct substitution of S-alkylthioether by amine is, however, easier to observe:
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• 19 Typical Procedure for 2a To solution of isovaleraldehyde (108 μL, 1.0 mmol) in DMF–MeCN (1:2; 0.6 mL, 1.6 M) was added, under argon atmosphere, allylamine (75 μL, 1.0 mmol), 6-mercaptopurine (152 mg, 1.0 mmol), and cyclohexyl isocyanide (125 μL, 1.0 mmol) respectively. The reaction contents were stirred and heated at 60 °C for 20 h, the solvents were removed under reduced pressure, and the crude reaction mixture was purified by flash column chromatography on silica gel (EtOAc–CH₂Cl₂, 10:90) to afford 2a as a white solid obtained in 58% yield (224 mg, 0.580 mmol); mp 185–186 °C; R_f = 0.4 (EtOAc–CH₂Cl₂, 40:60 ). ¹H NMR (400 MHz CDCl₃,): δ = 10.38 (br s, 1 H, NH), 8.46 (s, 1 H), 8.06 (s, 1 H), 6.44–6.30 (m, 1 H), 6.03 (ddd, J = 15.9, 10.1, 5.1 Hz, 1 H), 5.21 (d, J = 17.1 Hz, 1 H), 5.10 (d, J = 10.2 Hz, 1 H), 4.86–4.83 (m, 1 H), 4.59–4.56 (m, 1 H), 4.33–4.31 (m, 1 H), 2.09–2.06 (m, 3 H), 1.71–1.67 (m, 2 H), 1.62–1.49 (m, 3 H), 1.43–1.30 (m, 3 H), 1.24–1.17 (m, 2 H), 0.92 (d, J = 6.5 Hz, 3 H), 0.85 (d, J = 6.3 Hz, 3 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 200.0, 154.9, 151.6, 151.1, 136.9, 135.2, 119.0, 116.1, 61.4, 53.1, 46.6, 41.0, 31.1, 30.7, 25.6, 24.8, 24.3, 24.2, 22.8, 22.5. HRMS: m/z calcd for C₂₀H₃₀N₆S: 386.2253; found: 386.2244. IR (thin film): 3211, 3038, 2929, 2852, 1567, 1503, 1442, 1329, 1264, 1108 cm^–1.